Combination Therapy with Terbinafine and Amphotericin B in a Rabbit Model of Experimental Invasive Aspergillosis.

W.R. KIRKPATRICK, R.K. MCATEE, N.S. RYDER, and T.F. PATTERSON

Abstract:

Terbinafine, (Lamisil(r)}) an allylamine derivative which blocks ergosterol synthesis as a squalene epoxidase inibitor, was evaluated in an immunosuppressed temporarily neutropenic rabbit model of invasive aspergillosis. Ketoconazole, an imidazole which also blocks ergosterol synthesis, has been demonstrated to antagonize the activity of amphotericin B (AmB) in animal models of aspergillosis. Thus, clinical concerns exist about the possibility of antagonistic effects arising from combination therapy using AmB with agents which block ergosterol synthesis. In this study, terbinafine was evaluated alone and in combination with subtherapeutic doses of AmB to assess antagonism or synergy in this model. Therapy with oral terbinafine at 100 mg/kg/d, IV AmB at either 0.4 or 1.0 mg/kg/d and a combination of oral terbinafine at 100 mg/kg/d with AmB at 0.4 mg/kg/d was begun 24 hr after IV challenge with A. fumigatus in neutropenic rabbits and was continued for 5 d. Mortality occurred in 8/8 untreated controls vs 6/8 treated with terbinafine 100 and 3/8 with either dose of AmB or terbinafine/AmB combination. Tissue colony counts were reduced with both AmB doses and the terbinafine/AmB combination. All treatment regimens reduced mortality and increased the days of survival and as compared with controls. The terbinafine/AmB combination was more effective than the similar dose of terbinafine alone, and except for improved clearance of Aspergillus from lung tissue was similar to low dose AmB alone in the clearance of Aspergillus from tissues. In this model, Terbinafine had relatively little activity, but did not demonstrate antagonism against AmB. Combinations of antifungal agents may not be antagonistic and should continue to be evaluated for efficacy in invasive aspergillosis.